Cell microenvironments hold key to future stem cell therapies

Adult stem cells and their more committed kin, progenitor cells, are prized by medical researchers for their ability to produce different types of specialised cells. The potential of using these cells to repair or replace damaged tissue holds great promise for cancer therapies and regenerative medicine. However, the question that must first be answered is what determines the ultimate fate of a stem or progenitor cell? A team of researchers led by Berkeley Lab’s Mark LaBarge and Mina Bissell appear to be well on the road to finding out.

Working with unique microenvironment microarrays (MEArrays) of their own creation, LaBarge and Bissell and their collaborators have shown that the ultimate fate of a stem or progenitor cell in a woman’s breast – whether the cell develops normally or whether it turns cancerous – may depend upon signals from multiple microenvironments.

‘We found that adult human mammary stem and progenitor cells exhibit impressive plasticity in response to hundreds of unique combinatorial microenvironments,’ said LaBarge, a cell and molecular biologist in Berkeley Lab’s Life Sciences Division. ‘Our results further suggest that rational modulation of the microenvironmental milieu can impose specific differentiation phenotypes on normal stem or progenitor cells, and perhaps even impose phenotypically normal behaviour on malignant cells during tissue genesis. All of this points to the rational manipulation of adult stem and progenitor cells as a promising pathway for beneficial therapies.’

Previous studies on how microenvironments affect the development of adult human stem or progenitor cells have been based on the behaviour of these cells in culture (in vitro) where they are exposed to a single molecular agent. However, when these cells are in an actual human being (in vivo) they are surrounded by a multitude of other cells plus a supporting network of fibrous and globular proteins called the extracellular matrix (ECM), as well as many other nearby molecules, all of which may be simultaneously sending them instructional signals.

‘With our MEArrays, we can use combinations of proteins from a select tissue to create multiple microenvironments on a single chip about two square centimetres in area,’ said LaBarge. ‘We think this approach will give us a much more realistic picture as to how stem and progenitor cells actually behave in vivo.’

Said Bissell, a Distinguished Scientist with Berkeley Lab’s Life Sciences Division and one of the world’s leading researchers on breast cancer, ‘We have demonstrated that each discrete cell fate decision requires the integration of multiple pathways, and we have identified combinations of components in the human mammary microenvironment that impose distinct cell fates. These results are exciting because they indicate that we can test a large number of effectors and determine which ones to use to direct the fate of adult stem and progenitor cells. This give hope that one day – sooner rather than later – the information could be used for therapy.’

Collaborating with LaBarge and Bissell on this study were Jason Ruth, now at the University of Pennsylvania, Martha Stampfer of Berkeley Lab, Celeste Nelson, now with Princeton University, and Rene Villadsen, Agla Fridriksdottir and Ole Petersen, of the Panum Institute in Denmark.

Human breast tissue harbors two types of epithelial cells: luminal – the cells that are able to produce milk and generally the ones that become cancerous; and myoepithelial – the cells that surround the luminal cells and push milk down the ducts to the nipples, but which rarely become cancerous. Like cells in other types of tissue these breast epithelial cells are spawned from stem and progenitor cells that despite being primitive – essentially a cellular blank slate – possess the exact same genome as their differentiated daughters. Once it was widely held that adult stem and progenitor cells intrinsically ‘know’ when to self-renew and when to differentiate into one specific tissue cell or another based on pre-determined genetic programs. However, pioneering research by Bissell, in which it has been demonstrated that interactions between an epithelial breast cell and its ECM play a major role in determining whether that cell becomes cancerous, pointed the way to the idea that the ultimate fate of a stem or progenitor cell is heavily influenced by interactions with its neighboring microenvironments.

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